P421: LOWER VΓ9VΔ2 T CELLS RELATIVE FREQUENCIES PREDICT POORER SURVIVAL IN NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA
Authors: A.-C. Le Floch, F. Orlanducci, A. Le Roy, J.-F. Hamel, N. Ifrah, P. Cornillet-Lefebvre, J. Delaunay, C. Récher, E. Delabesse, A. Pigneux, M.-C. Béné, N. Vey, A.-S. Chretien, D. Olive
Journal: HemaSphere (2022)

Background: Major role of γδ T cells has recently emerged in anti-tumor immunity. Across several tumor subtypes, increased relative frequencies of γδ T cells had the best prognostic value in comparison to other immune subsets. In acute leukemias, patients with increased γδ T cells reconstitution after allogenic stem cell transplantation had better outcomes. The less studied putative prognostic impact of Vγ9Vδ2 T cells abundance in newly diagnosed (ND) AML relies almost on inference of transcriptomic data or post induction frequencies and has not been assessed with respect to other confounding factors. Aims: The aim of this study was to determine the predictive and prognostic impact of blood Vγ9Vδ2 T cells frequencies at diagnosis, as measured using phenotypic analysis, taking into account biological and clinical parameters in patients treated for AML with induction. Methods: Proportion of Vγ9Vδ2 T cells among lymphocytes has been assessed by flow or mass cytometry on PBMCS from AML patients at diagnosis, obtained from the Department of Hematology of Institut Paoli Calmettes or from the tumor bank of the FILO group. Correlations between clinical outcome, patient or disease characteristics, and Vγ9Vδ2 T cells frequencies have been analyzed. For some of the samples, we characterized immune alterations displayed by Vγ9Vδ2 T cells, or performed Vγ9Vδ2 T cell expansion and degranulation assays of autologous Vγ9Vδ2 T cells. Results: 198 patients were included in this study. Mean age was 56 years [18.9-81.5], 79 (39.9%) and 119 (60.1%) patients had respectively a favorable or an intermediate ELN classification. Mean CR rate was 81.3%. Analysis of overall survival (OS) and relapse free survival (RFS) based on Vγ9Vδ2 T cell frequencies among lymphocytes, highlighted that the 0.8% threshold was the most significant. Vγ9Vδ2 T cells relative frequencies were considered low for values below this threshold. By univariate analysis, patients with lower Vγ9Vδ2 T cells at diagnosis had significantly lower 5-year OS and RFS (HR = 1.54, 95%CI = 1.03-2.31, p = 0.028 and HR = 1.69, 95%CI = 1.09-2.62, p = 0.015). These results were confirmed in multivariate analysis (HR = 1.55 [1.04-2.30], p = 0.030 and HR = 1.64 [1.06, 2.53], p = 0.025). Phenotypic alterations found in patients with lower Vδ2 included a loss of some cytotoxic Vγ9Vδ2 T cell subsets and a decrease in BTN3A expression on the surface of blasts. Finally, in vitro, samples irrespective of their Vγ9Vδ2 T cells numbers did expand and displayed similar functional effects against target cells after stimulation with zoledronate or anti-BTN3A 20.1 agonist mAb. Summary/Conclusion: This study confirmed the prognostic value of Vγ9Vδ2 T cells predominance among lymphocytes, in ND AML patients treated with induction. Vγ9Vδ2 T cells frequencies could be easily included in algorithm of treatment decision. Our findings contribute also to a strong rationale to elaborate consolidation protocols targeting enhancement of Vγ9Vδ2 T cells response, such as anti-BTN3A agonist antibodies that are under development (Marabelle et al. ESMO 2021).